Dithioacid esters



United States Patent ABSTRACT OF THE DISCLOSURE Dithiocarbamates of the formula S=CR1 (kHz-R2 one of R =monoor bicyclic alk(en)yleneimino, aza-, oxaor thiaalkyleneimino, the other=di-lower alkylamino salts and lower alkyl-ammonium derivatives thereof are active against bacteria, fungi and coccidia.

The present invention concerns and has for its object the provision of dithiocarbamic acid aminomethyl esters and methods for their preparation.

More particularly the invention comprises dithiocarbamates of the formula in which the one of R and R stands for di-lower alkylamino and the other for alkyleneimino, alkenyleneimino, mono-aza-, oxaor thia-alkyleneimino, bicycloalkyleneimino, bicycloalkenyleneirnino or benzalkyleneirnino or both R and R stand for the same or for different of said cyclic imino radicals, of which R and R being 1,5- pentyleneimino and/ or 3-oxa-l,S-pentyleneimino, at least one thereof contains at least one additional substituent, salts and lower alkylamnronium derivatives thereof.

Said radicals R and R may or must contain one or more than one of the same or of different substituents, such as lower alkyl groups and/or free or functionally converted hydroxy, mercapto, amino and/or carboxy groups, e.g. methyl, ethyl, nor isopropyl, n-, iso-, sec.- or tert.-butyl, lower alkoxy, such as methoxy, ethoxy, npropoxy or n-butoxy, halogen, such as fiuoro, chloro or bromo, lower alkylmercapto, such as methylor ethylmercapto, di-lower alkylamino, such as d-imethylamino, diethylamino or di-n-propylamino, carbo-lower alkoxy, such as carbomethoxy or carbethoxy, or carbamyl.

A di-lower alkylamino group R or R represents, for example, one of the above mentioned groups, but also N-methyl-N-ethylamino, N-methyl-N-n-propylamino, diisopropylamino, N-ethyl-N-n-butylamino, N-methyl-nisobutylamino, di-n-butylamino, di-n-pentylamino, di-nhexylamino or di-n-heptylamino.

An alkyleneimino or alkenyleneimino group, more particularly contains two to ten, preferably four or five, ringcarbon atoms and represents, for example, ethyleneimino, pyrrolidino, piperidino, 1,4-pentyleneimino 3- methyl-1,5-pentyleneimin0, 1,5-, 2,5- or 1,6-hexyleneimino, 1,7- or 2,6-heptyleneimino, 1,8-octyleneimino, 1,9- nonyleneimino or 1,10-decyleneirnino; 3pyrrolirro, 2- methyl-1,4-but-2-enyleneirnino, 1,5-pent-2-enyleneimino, 1,6- or 2,5-hex-3-enyleneimino, l,6-hept-3-enyleneimino or 1,8-oct-4-enyleneirnino.

A mono-aza-alkyleneimino group more particularly contains six to ten, preferably six ring members, both nitrogen atoms being separated from each other by at least two ring-carbon atoms. Examples are N-lower alkyl 3,449,360 Patented June 10, 1969 or monocyclic carbocyclic aryl-aza-alkyleneimino groups, such as N-methyl-, N-ethyl-N-propyl-, N-isopropyl-, N-butyl-, N-phenyl, N-(lower alkyl)-phenyl-, N-(lower alkoxy)-phenyl-, N(halogen0)-phenyl, N- (trifluoromethyl)-phenyl, N-(nitro)-phenylor N- (amino)-phenyl-piperazino, -2,6-dimethyl-piperazino, -3- aza-l,6-hexyleneimino, -4-aza-1,7-heptyleneimino or -4- aza-1,8-octyleneimino.

A mono-ozaor thia-alkyleneimino group more particularly also contains six to ten, preferably six ring members, the oxygen or sulfur atom being separated from the imino group by at least two ring-carbon atoms, such as morpholino, 2,6-dimethyl-morpholino, thiamorpholino, 3-oxaor thia-l,6-hexyleneimino, 4-oxaor thia- 1,7-heptyleneimino or 4-oxa- .or thia-l,8-octyleneimino.

Bicycloalkyleneimino or bicycloalkenyleneimino groups preferably have the formula in which A stands for 1,2-ethylene, 1,3-propylene, 1,4- butylene, 1,2-ethenylene, 1,3-pr0penylene or 1,4-but-2- enylene, each of R R R and R for hydrogen or methyl, each of m and n for an integer from 0 to 3 and p for an integer from O to 2, with the proviso that both rings I and II have at least five ring members and together from six to ten ring carbon atoms. Examples are the following: 2-(2-aza-bicyclo[2,2,1]heptyl), 7-(7-aza-bicyclo[2,2,l]heptyl), 3-(3-aza-bicyclo[3,3,0]octyl), 2-(2- aza-bicyclo [2,2,2 octyl 2- 2-aza-bicyclo [3 ,2,1]octyl) 3-(3-aza-bicyclo[3,2,l]octyl), 3-(1,8,8-trimethyl-3-azabicyclo[3,2,l]octyl), 6-(6-aza-bicyclo[3,2,1]octyl), 8-(8- aza-bicyclo[3,2,1]octyl), 2-(2-aza-bicyclo[4,3,0]nonyl), 7-(7-aza-bicyclo[4,3,0]nonyl), 8-(8-aza-bicyclo[4,3,0] nonyl), 3-(3-aza-bicyclo[3,3,1]nonyl), 3 (3 aza bicyclo [3,2,2]nonyl), 2-(2-aza-bicyclo[4,4,0]decyl), 3-(3-azabicyclo [4,4,0] decyl) 2- 3-methyl-2-aza-bicyclo [4,4,0'] decyl), l0-(10-aza-bicyclo[4,3,1]decyl), 8-(8-aza-bicyclo [4,3,1]decyl) or 2-(2-aza-bicyclo [4,3,1]decyl).

A benzalkyleneirnino group preferably has the formula I Ph I oumn in which Ph stands for 1,2-phenylene, (lower alkyl)-1,2- phenylene, (lower alkoxy)-l,2-phenylene, (halogeno)-l, Z-phenylene, (trifluoromethyl) -1,2-phenylene, (nitro -1, 2-phenylene or (amino)-l,2-phenylene and the remaining groups have the previously given meaning, i.e. representing a direct bond, methylene, 1,1- or 1,2-ethylene, 1,1-, 1,2-, 1,3- or 2,2-propylene, with the proviso that the azacyclic ring contains at least five ring members.

The compounds of this invention possess valuable pharmacological properties. For example, they exhibit antibacterial and antifungal activity, especially against microorganisms causing coccidiosis, such as Eimeria tenella, Eimeria (ICEI'VHliflflJ and Eimeria necatrix. They are, therefore, useful in the treatment and prevention of bacterial and fungal infections, particularly of coccidiosis in poultry, e.g. in chickens. The compounds of this invention are also useful as starting materials, intermediates or expedients in the manufacture of other valuable products. Particularly useful are compounds of the formula shown in the beginning, in which one of R and R stands for dialkylamino in which alkyl has up to four carbon atoms and the other for lower alkyleneimino or lower alkenyleneimino having from four to five ring-carbon atoms, N-lower alkyl-piperazino, N-phenylpiperazino, N-(lower alkyl)-phenyl-piperazino, N- (halogeno) -phenylpiperazino, N-(nitro)-phenyl-piperazino, bicycloalkyleneimino in which each ring contains from five to six ring members, l-indolinyl, 2-isoindolinyl, l-(1,2,3,4- tetrahydro-quinolyl) or 2-(1,2,3,4-tetrahydro-isoquinolyl), or both R and R stand for the same or for different of said cyclic imino radicals, of which R and R being 1,5-pentyleneimino at least one thereof contains a carbamyl group, and salts thereof.

The compounds of the invention are prepared accord-. ing to methods in themselves known. For example, the process for their preparation consists in:

(a) reacting the formaldehyde adduct of the amine R H and/or R H with carbon 'disulfide or (b) reacting the dithiocarbamate of the formulae with formaldehyde or the formaldehyde adduct of the amine R H and, if desired, converting a free compound obtained into a salt or quaternary lower alkyl ammonium derivative thereof or converting a salt obtained into the free compound or into another salt.

In the above reaction the formaldehyde preferably is used in the form of an aqueous solution having a strength, for example, of about 30 to 40%, but may also be used in another form, e.g. the gaseous state. The formaldehyde-amine adducts may either be the corresponding amino-methanols or diamino-methanes.

The process is carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, preferably alcohols, such as lower alkanols, e.g. ethanol, of catalysts, condensing agents and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure.

The compounds of the invention are obtained in the free form or in the form of their salts, dependingon the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalis or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic carboxylie or sulfonic acids, for example, formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleie, hydroxymaleie, pyroracemic, phenylacetic, benzoic, aminobenzoic, anthranilic, hydroxybenzoic, salicyclic, aminosalicyclic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonie, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonie and sulfanilic acid; methionine, tryptophane, lysine and arginine.

These or other salts of the new compounds, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Quaternary ammonium derivatives are prepared, for example, by treating the free compounds with a reactive ester of a lower alkanol, preferably a lower alkyl halide, according to known methods.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components may be used in the form of their salts.

Mainly, those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being especially valuable.

The starting materials are known or, if new, may be prepared according to the procedures described in my copending application Ser. No. 433,447 filed concurrently with the present application.

The new compounds can be used in the free form or in the form of their salts, for example, for the manufacture of pharmaceutical preparations containing the said compounds in admixture with organic or inorganic, solid or liquid pharmaceutical excipients suitable especially for enteral but also for parenteral administration. Suitable excipients are substances that do not react with the new compounds, for example, water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, propylene glyeols, White petroleum jelly and other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees or capsules, or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or buffers. They may further contain other therapeutically valuable substances. The pharmaceutical preparations are prepared by conventional methods.

The present invention also comprises animal feed compositions essentially of an effective amount of a compound of this invention as the active coccidiostatic ingredient, together with a balanced feed formulation as the carrier. Especially useful as active coccidiostatic ingredients in the feed compositions of this invention are the compounds previously mentioned as being the preferred embodiments.

The feed compositions of this invention have from about 0.01 percent to about 0.2 percent, more especially from about 0.01 percent to about 0.1 percent of the active coccidiostatic ingredient. Apart from the above-mentioned active coccidiostatic ingredients, the feed compositions contain the usual feed components, such as grains, protein supplements, mineral supplements, antimicrobial agents, particularly antibiotics, and other useful substances in ratios and proportions known to be best adaptable to the particular feed. Examples of suitable feed constituents include barley, barley meal, buckwheat, com, corn meal, kafir, oats, oat groats, ground oats, rolled oats, rye, wheat, wheat bran, wheat shorts, wheat middlings, milk, boned meal, meat meal, meat scrap, corn gluten mean, oil cake meal, soybean meal, dried whey, fish meal, dried distillers solubles, alfalfa, dehydrated alfalfa meal, clover, grass clippings, caggage, kale, cod liver oil, and similar nutrients, as well as mineral supplements, such as dicalcium phosphate, calcium carbonate iodized salt, manganese sulfate, zinc salts, cobalt salts, iron salts, copper salts and the like, vitamins, e.g. vitamin A, niacin, calcium pantothenate, thiamine, riboflavin, vitamin B ascorbic acid, vitamin D, vitamin E and the like, other essential supplements, e.g. butylated hydroxytoluene, methionine and the like, antimicrobial agents, particularly antibiotics, e.g. bacitracin, penicillins, tetracycline, chlortetracycline, oxytetracycline, erythromycin and the like.

Preferably, a pre-mix containing the active coccidiostatic ingredient is formed together with a suitable carrier. Carrier substances are, for example, wheat middlings, starch, sucrose, lactose, mannitol, sodium gluconate, solvent extracted soybean feed or any other suitable blender; other auxiliary substances, such as buffers and buffer systems, e.g. citric acid-sodium citrate, sodium acetate, dipotassium phthalate-phthalic acid, sodium 'benzoatebenzoic acid, sodium lactate-lactic acid or sodium fumarate-fumaric acid, sequestering agents, such as salts of ethylenediamine tetra-acetic acid, e.g. ethylenediamine tetra-acetic acid tetra-sodium salt, which may be in admixture with a small amount of the mono-sodium salt of N,N-bis-(Z-hydroxyethyl)-glycine, or any other suitable agents, such as antoxidants or stabilizers. A premix contains from about 0.1 to about 20 percent, more especially from 0.5 to about 10 percent, of the active ingredient together with a suitable mixture of carrier and auxiliary substances.

The medicated feed composition is prepared according to standard procedures by adding the premix in amounts to make up the desired concentration of the active ingredient in the final medicated feed.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 To 113.6 g. of pyrrolidine 67.2 g. of a 36% aqueous solution of formaldehyde are added dropwise with stirring at to After one hour 49.6 ml. of carbon disulfide are added in such a rate that the temperature maintains between and 20. After an additional hour of stirring the obtained pyrrolidino-methyl N,N-1,4- butylene-dithiocarbamate of the formula is filtered off and recrystallized twice from ethanol, M.P. 72-73.5.

Example 2 separates and is recrystallized from isopropanol, M.P. 725-74.

'Example3 36.5 g. of diethylamine are added dropwise with stirring to 40.3 g. of 37.3% aqueous solution of formaldehyde at ice bath temperature. The mixture thus obtained is added within half an hour to the stirred suspension of 72.0 g. of pyrrolidinium N,N-1,4-butylene-dithiocarbamate in 150 ml. of anhydrous ethanol at room temperature. Stirring is continued for another half hour and hereupon the reaction mixture is cooled. The diethylamino-methyl N,N-1,4-butylene-dithiocarbamate of the formula obtained is filtered off and recrystallized twice from isopropanol, M.P. 73-74". N

Example 4 The mixture of 5.0 g. of pyrrolidino-methyl N,N-1,4- butylene-dithiocarbamate, 3.0 g. of methyl iodide and ml. of methylene chloride is refluxed for one hour with stirring. The precipitated methyl-pyrrolidiniummethyl N,N-1,4-butylene-dithiocarbamate iodide of the formula is filtered off and recrystallized from methanol-diethylether, M.P. 127-129.

Example 5 8.4 g. of a 36.3% aqueous formaldehyde solution is added dropwise with stirring to 13.8 g. of 3-pyrroline at 0 to 5. After one hour 6.2 ml. of carbon disulfide are added to the stirred mixture and the temperature is kept between 10 and 20". After an additional hour the obtained pyrrolinyl-methyl N,N-1,4-but-2-enylene-dithiocarbamate of the formula is filtered off and recrystallized from a small amount of ethanol, M.P. 65-67".

Example 6 is filtered off and recrystallized from isopropanol, M.P. 40-415".

Example 7 6.3 g. of a 36% aqueous formaldehyde solution is added dropwise with stirring to 17.0 g. of 1,7-heptyleneimine at 0-5 After one hour 4.7 ml. carbon disulfide are added and the temperature of the reaction mixture is kept below 20. After one hour of stirring the formed 1,7- heptyleneimino-methyl N,N 1,7 heptylene-dithiocarbamate of the formula is filtered off and recrystallized from ethanol, M.P. 63- 63.5".

Example 8 To 17.6 g. of N-(Z-methyl-phenyl)-piperazine 4.2 g. of a 36% aqueous solution of formaldehyde are added dropwise with stirring between 0 and 5. After one hour 3.1 ml. carbon disulfide are added to the stirred mixture and the temperature is kept below 20. The so-o'btained N (3 methyl phenyl) piperazino -methyl 3 (3 methyl-phenyl) 3 aza-1,6-hexylene-dithiocarbamate of the formula \N-SS--CH2N N is filtered off and recrystallized from ethanol-ethyl acetate, M.P. 163165.

Example 9 6.3 g. of a 36% aqueous formaldehyde solution are added dropwise with stirring to 16.7 g. of 2-aza-bicyc1o- [2,2,2]octane at 0 to 5". After one hour 4.7 ml. of carbon disulfide are added to the stirred reaction mixture, the temperature of which is kept between l0 and 20. The precipitated 2 (2 aza-bicyclo[2,2,2]octyl)-methyl 7 N,N 1,4 ethano-l,5-pentylene-dithiocarbamate of the formula is filtered off and recrystallized from ethyl acetate, M.P. 148-149".

Example 10 NCSSOHzN is filtered off after one hours stirring and recrystallized from ethanol, M.P. 9899.

Example 11 In the analogous manner described in the previous examples the following compounds are prepared from equivalent amounts of the corresponding starting materials: 3 carbamyl-piperidino-methyl N,N 1,4 butylene-dithiocarbamate, 4-carbamyl-piperidino-methyl N,N- 1,4 butylene dithiocarbamate, 2 (2 aza bicyclo- [2,2,2]octyl methyl N,N diethyl dithiocarbamate, 2- (1,2,3,4 tetrahydro isoquinolyl) methyl N,N-1,4- butylene dithiocarbamate, pyrrolidino methyl N,N-1,2- benzo 1,6 hexylene dithiocarbamate, morpholino methyl N,N di n butyl dithiocarbamate, di n propylamino -methyl N,N 3 thia 1,6 hexylene dithiocarbamate, dimethylamino methyl N,N 1,4 but 2 enylene dithiocarbamate and pyrrolidino methyl N,N 2,5 ethano 1,6 hex 3 enylene dithiocarbamate.

Example 12 A poultry feed containing 0.025 percent of the active ingredient is prepared as follows:

Premix: G.

Pyrrolidino-methyl N,N-1,4-butylenedithiocarbamide 5.0 Wheat standard middlings (30-80 mesh) 995.0

The above ingredients are thoroughly mixed in an appropriate mixing equipment, and the resulting premix is then added to the feed formula in desired quantities.

Feed formula: G. Corn meal (No. 2 yellow) 1,062.875

Calcium carbonate 20.000 Iodized salt 10.000

Vitamins A & D (1,000,000 A & 250,000

D USP units/pound) 4.000 Calcium pantothenate 0.250 Butylated hydroxy-toluene 0.250 Choline chloride 25% 2.500 Riboflavin cone. (24 g. per pound) 0.125 Vitamin B (0.02 g. per pound) 1.000 DL-methionine (or the hydroxy analog) 0.500 Manganese sulfate 0.500

Total weight 2,000.000

The feed formula is prepared as follows: A portion of the corn meal is introduced into the blending machine (about half of the amount to be added). The remaining corn meal, previously blended with the pre-heated, liquified fat, is added thereto and mixing is continued until uniformity is obtained. The manganese sulfate, di-calcium phosphate, calcium carbonate and iodized salt are then added with mixing, followed by the addition of the fish meal, soy bean meal, corn gluten meal, alfalfa meal and corn distiller solubles. After a uniform mixture has been obtained, vitamins A and D, calcium pantothenate, choline chloride, riboflavin, Vitamin B and methionine are added in that order. Mixing is continued after the addition of butylated hydroxy-toluene, and maintained until a uniform product is obtained.

The premix is added to the above feed formula in an amount sufficient to provide a concentration of 0.25 g. of the active ingredient per 1,000 g. of feed in the uniformly blended mix.

What is claimed is:

1. A member selected from the group consisting of dithiocarbamates having the formula R1- 3-s-GH,R, in which each of R and R stands for monocyclic alkenyleneimino with 4 to 8 carbon atoms, a quaternary lower alkylammonium derivative and a therapeutically useful acid addition salt thereof.

2. A member selected from the group consisting of dithiocarbamates having the formula Rr-(lL-S-CHrRa in which each of R and R stands for a member selected from the group consisting of 3-pyrrolino, 2-methyl-1,4- but 2 enyleneimino, 1,5 pent 2 enyleneimino, 1,6- hex 3 enyleneimino, 2,5 hex 3 enyleneimino, 1,6- hept 3 enyleneimino and 1,8 oct 4 enyleneimino and a therapeutically useful acid addition salt thereof.

3. 3 pyrrolinyl-methyl N,N-1,4-but-2-enylene-dithiocarbamate.

References Cited UNITED STATES PATENTS 2,325,720 8/1943 Urbschat et al. 260293.4

ALTON D. ROLLINS, Primary Examiner.

U.S. Cl. X.R. 

